19-50423008-G-T

Variant names:

• chr19-50423008-G-T
• rs11546996
• NM_003121.5:c.310G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003121.5(SPIB):​c.310G>T​(p.Ala104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A104P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797
• Publications: 25 publications found

Genes affected

SPIB (HGNC:11242): (Spi-B transcription factor) The protein encoded by this gene is a transcriptional activator that binds to the PU-box (5'-GAGGAA-3') and acts as a lymphoid-specific enhancer. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14486673).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003121.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPIB	NM_003121.5	MANE Select	c.310G>T	p.Ala104Ser	missense	Exon 4 of 6	NP_003112.2
	SPIB	NM_001243999.2		c.310G>T	p.Ala104Ser	missense	Exon 4 of 6	NP_001230928.1
	SPIB	NM_001244000.2		c.252G>T	p.Leu84Leu	synonymous	Exon 4 of 6	NP_001230929.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPIB	ENST00000595883.6	TSL:1 MANE Select	c.310G>T	p.Ala104Ser	missense	Exon 4 of 6	ENSP00000471921.1
	ENSG00000142539	ENST00000599632.1	TSL:5	c.712G>T	p.Ala238Ser	missense	Exon 8 of 10	ENSP00000473233.1
	SPIB	ENST00000270632.7	TSL:1	c.310G>T	p.Ala104Ser	missense	Exon 4 of 6	ENSP00000270632.7

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151314 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000219 AC: 3 AN: 1372538 Hom.: 0 Cov.: 27 AF XY: 0.00000147 AC XY: 1 AN XY: 678318

African (AFR) AF: 0.00 AC: 0 AN: 30572

American (AMR) AF: 0.00 AC: 0 AN: 32780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21634

East Asian (EAS) AF: 0.00 AC: 0 AN: 38568

South Asian (SAS) AF: 0.00 AC: 0 AN: 75932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4690

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1061966

Other (OTH) AF: 0.00 AC: 0 AN: 56438

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151314 Hom.: 0 Cov.: 27 AF XY: 0.0000135 AC XY: 1 AN XY: 73830

African (AFR) AF: 0.00 AC: 0 AN: 41200

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67740

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00 Hom.: 4146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.3
DANN	Benign	0.59
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.80
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.028
Sift	Benign	0.44	T
Sift4G	Benign	0.48	T
Polyphen		0.020	B
Vest4		0.21
MutPred		0.19		Gain of glycosylation at A104 (P = 0.0108)
MVP		0.48
MPC		0.024
ClinPred		0.17	T
GERP RS		-2.1
Varity_R		0.049
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11546996; hg19: chr19-50926265;